Use of 1-adamantylethyloxy-3-morpholino-2-propanol or pharmaceutically acceptable salts thereof in pharmaceutical compositions as a neuroretinal protector

ABSTRACT

The use of 1-adamantylethyloxy-3-morpholino-2-propanol, or pharmaceutically acceptable salts thereof, in a concentration range of from 3 to 100 mg/ml in pharmaceutical compositions for parenteral administration in the treatment of degenerative neuroretinal diseases of various geneses.

This application is a national stage application, filed under 35 U.S.C.§371, of International Application No. PCT/UA2013/000106, filed Sep. 17,2013, which claims priority to Ukrainian Application No. 2012 11512,filed Oct. 5, 2012, and Ukrainian Application No. 2013 10844, filed Sep.9, 2013, the contents of all of which as are being hereby incorporatedby reference in their entirety.

The invention relates to medicine and pharmacy and concerns apharmaceutical composition for parenteral use comprising1-adamantylethyloxy-3-morpholino-2-propanol or pharmaceuticallyacceptable salts thereof as a neuroretinoprotector which may be used inpharmaceutical compositions for parenteral use, within the concentrationrange of 3-100 mg/ml.

The pathology of the retina and optic nerve occupies the significantplace among the causes of sight-disabled persons. According to modernideas ischemia is one of main pathogenetic components and a trigger thatcauses the most severe diseases of the retina and optic nerve, such ascentral retinal artery occlusion, optic neuropathies, includingglaucoma, at age-associated macular degeneration, myopic retinaldegeneration etc.

However, existing agents for pharmacotherapy of said diseases such asvasoactive drugs (aminophylline, vinpocetine, nicotinic acid, andpentoxifylline), fibrinolytic agents and enzymes (fibrinolysin),anticoagulants (heparin), antiplatelet agents (acetylsalicylic acid),antihypoxants (etylmetylhydroxy pyridine succinate), nootropic agents(piracetam), calcium channel blockers (nimodipine, nifedipine),antioxidants, vitamin preparations and their complexes (emoxypine,vitamins A, C and B group), hormones and anabolic steroids, tissuetherapy drugs, polypeptide bioregulators and others are not alwayssufficiently effective and may not fully protect or restore thestructure and function of eye ischemic tissues. At the same time thepresence of adverse effects in existing drugs often limit their use andgive rise to various complications. That is, at present, from aprospective of evidence-based medicine, the world lack neuroprotectivereference product with proven efficacy for treatment of destructivedegenerative diseases of the retina and optic nerve.

According to modern ideas for protection of the retina and optic nerve(neuroprotection) the use of adamantane derivatives, includingmemantine, may be the most encouraging and promising due to the abilityto delay retinal cell death by binding NMDA with glutamate receptorsleading to discontinuation of prolonged penetration of Ca²⁺ ions havingcytotoxic effect, inside them. This mechanism of injury is one of theleading in the development of many diseases of the eye, especiallyglaucoma. However, the clinical success may only be achieved by usingthe NMDA-receptor antagonist that selectively reduce their excessiveactivation as physiological activity of NMDA-receptor is required fornormal retina functioning.

The basis for development of a pharmaceutical composition for parenteraluse comprising the active substance1-adamantylethyloxy-3-morpholino-2-propanol or pharmaceuticallyacceptable salts thereof within the concentration range of 3-100 mg/mlis that it has the properties of fast blocking/unblockingNMDA-receptors. This may indicate to the protective effect thereof onischemic retina and optic nerve and makes it promising (as opposed tonon-competitive NMDA-receptor blockers) and safer as neuroprotectiveproduct.

The task of claimed utility model is to make a pharmaceuticalcomposition for parenteral use comprising the active substance1-adamantylethyloxy-3-morpholino-2-propanol or pharmaceuticallyacceptable salts thereof within the concentration range of 3-100 mg/mlto improve pharmacotherapy of neuroprotective diseases of variousgeneses.

The proposed pharmaceutical composition may be used under occlusion ofretina blood vessels, optic neuropathies including glaucoma, atage-associated macular degeneration, myopic retinal degeneration,diabetic and glaucoma retinopathy, eye circulatory disorders,degenerative diseases of retina and optic nerve including its atrophyand subatrophy, retinal detachment before and after surgery on the eye,as well as at various injuries thereof.

EXAMPLE 1

The experimental treatment of rats with ischemia-reperfusion eye modelwith pharmaceutical composition for parenteral use comprising the activesubstance 1-adamantyletyloksy-3-morpholino-2-propanol orpharmaceutically acceptable salts thereof within 96 hours of ischemia atdoses of 3; 5; 10; 20 and 100 mg/kg reduces the number of apoptotic andnecrotic cells in eye posterior part, and perivascular edema isattenuated in the retina and optic nerve, which provides the protectionfrom the destructive effects of ischemia and reperfusion of all retinalayers (photoreceptor, outer and inner nuclear, inner retinal, includingganglion, which is the most sensitive to ischemia. It evidences theappropriateness for use of proposed pharmaceutical composition underconditions of retina blood vessels occlusion, optic neuropathiesincluding glaucoma, at age-associated macular degeneration, myopicretinal degeneration, diabetic and glaucoma retinopathy, eye bloodsupply disturbance, degenerative diseases of retina and optic nerveincluding its atrophy and subatrophy, retinal detachment before andafter eye surgery as well as variety of eye injuries.

EXAMPLE 2

Experimental therapy of rats with ischemia-reperfusion eye model withpharmaceutical composition for parenteral use comprising the activesubstance 1-adamantylethyloxy-3-morpholino-2-propanol orpharmaceutically acceptable salts thereof within 96 hours of ischemia atdoses of 3; 5; 10; 20 and 100 mg/kg promoted the normalization ofdisturbed indicators of acid-alkali balance, oxidative stress and energymetabolism in ischemic brain.

This demonstrates the appropriateness for use of proposed pharmaceuticalcomposition at f retina blood vessels occlusion, optic neuropathiesincluding glaucomous.

EXAMPLE 3

Experimental treatment of rats with ischemia-reperfusion eye model withpharmaceutical composition for parenteral use comprising the activesubstance 1-adamantyletyloxy-3-morpholino-2-propanol or pharmaceuticallyacceptable salts thereof within 96 hours of ischemia at doses of 3; 5;10; 20 and 100 mg/kg promoted the reduction in retinal manifestations ofendothelial dysfunction and nitrosating stress. This demonstrates theappropriateness for use of proposed pharmaceutical composition at retinablood vessels occlusions, optic neuropathies including glaucomous,diabetic and glaucoma retinopathy, circulatory eye disorders and retinaldetachment.

EXAMPLE 4

Experimental therapy of rats with ischemia-reperfusion eye model withpharmaceutical composition for parenteral use comprising the activesubstance 1-adamantylethyloxy-3-morpholino-2-propanol orpharmaceutically acceptable salts thereof within 96 hours of ischemia atdoses of 3; 5; 10; 20 and 100 mg/kg promoted the normalization ofdisturbed indicators of acid-alkali balance, oxidative stress and energymetabolism in the retina. This demonstrates the appropriateness for useof proposed pharmaceutical composition at retina blood vesselsocclusion, optic neuropathies including glaucomous, diabetic andglaucoma retinopathy, circulatory eye disorders and retinal detachmentbefore and after surgery on the eye, but also and at various injuriesthereof.

EXAMPLE 5

Studies in rats have found that the use of the pharmaceuticalcomposition for parenteral use comprising the active substance1-adamantylethyloxy-3-morpholino-2-propanol or pharmaceuticallyacceptable salts thereof at intravenous administration to rats at dosesof 3; 5; 10; 20 and 100 mg/kg stimulates blood circulation in thecentral eye artery under conditions of its model ischemia-reperfusion.

The ability of the pharmaceutical composition for parenteral usecomprising the active substance1-adamantylethyloxy-3-morpholino-2-propanol or pharmaceuticallyacceptable salts thereof to improve eye blood circulation demonstratesthe appropriateness of its use in retina blood vessels occlusion, opticneuropathies including glaucomous, at age-associated maculardegeneration, myopic retinal degeneration, diabetic and glaucomaretinopathy, eye circulatory disorders, degenerative diseases of theretina and optic nerve including its atrophy and subatrophy, retinaldetachment before and after surgery on the eye, as well as and atvarious injuries thereof.

Thus, the results of the studies show that the active ingredient andpharmaceutical composition for parenteral use comprising the activesubstance 1-adamantylethyloxy-3-morpholino-2-propanol orpharmaceutically acceptable salts thereof within the concentration rangeof 3-100 mg/ml have expressed neuroprotective properties under theconditions of ishemic-hypoxic injury of retina and optic nerve. Thisgives grounds to their use in clinical practice under the conditions ofretina blood vessels occlusion, optic neuropathies including glaucomous,at age-associated macular degeneration, myopic retinal degeneration,diabetic and glaucoma retinopathy, eye circulatory disorders,degenerative diseases of retina and optic nerve including its atrophyand subatrophy, retinal detachment before and after surgery on the eyeas well as various injuries thereof.

1. The use of 1-adamantylethyloxy-3-morpholino-2-propanol orpharmaceutically acceptable salts thereof in pharmaceutical compositionsas a neuroretinoprotector.
 2. The use according to claim 1, wherein the1-adamantylethyloxy-3-morpholino-2-propanol or the pharmaceuticallyacceptable salts thereof are contained in pharmaceutical compositionswithin the concentration range of from 3-100 mg/ml.
 3. The use accordingto claim 1 for treatment of retina blood vessel occlusion, opticneuropathies including glaucomous, at age-associated maculardegeneration, myopic retinal degeneration, diabetic and glaucomaretinopathy, eye circulatory disorders, degenerative diseases of retinaand optic nerve including its atrophy and subatrophy, retinal detachmentbefore and after surgery on the eye as well as various injuries thereof.4. The use according to claim 2 for treatment of retina blood vesselocclusion, optic neuropathies including glaucomous, at age-associatedmacular degeneration, myopic retinal degeneration, diabetic and glaucomaretinopathy, eye circulatory disorders, degenerative diseases of retinaand optic nerve including its atrophy and subatrophy, retinal detachmentbefore and after surgery on the eye as well as various injuries thereof.